Summary. Bacterial pneumonia is a leading cause of mortality and morbidity worldwide. Even with antibiotic treatments, many patients still rapidly progress to severe illness requiring hospitalization, intensive care, and prolonged recovery. The pathobiology of bacterial pneumonia is characterized by robust host immune responses that cause airway damages. Whereas host defense and immunity to bacterial lung infections have been extensively studied, little is known about which cells are injured and what role tissue repair and regeneration play in recovery from bacterial pneumonia. Studies using mouse models with physical and chemical injuries have shown that regenerative process in the lung parenchyma depends on proliferation and differentiation of local stem or progenitor cells, which include the type I (AECI) and type II (AECII) alveolar epithelial cells, and bronchiolar Club cells. Defects in their regenerative capacity have been implicated in severe chronic pathological conditions, including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and emphysema. Numerous pathways important for tissue growth, patterning and differentiation during embryonic development are redeployed in the process of regeneration to repair tissue injury in adults. Our previous work has shown that the miRNA302 cluster promotes proliferation of lung epithelial progenitor cells during development. The miRNA302 functions, in part, by repressing expression of key components (Mst1, and Last2) of the kinase cascade in the Hippo signaling pathway, which in turn regulates expression of genes involved in cell proliferation, apoptosis and differentiation. Our preliminary studies showed that mice infected with Streptococcus pneumoniae (Sp) had substantial injuries in the lung parenchyma followed by visible alveolar epithelial regeneration. However, full repair took an extended period of time (>30 days). We also found increased expression of miR302 in the lung epithelium and proliferation of resident AECI and AECII cells in response to lung injury from Sp infection. Furthermore, administration of small molecule miRNA302-mimics to Sp-infected mice promoted airway epithelial regeneration, resulting in improved lung function, enhanced mouse recovery and better survival. Based on these results, this R21 project will rigorously test the hypothesis that targeting microRNA-Hippo pathway may provide a novel therapeutic approach to promote alveolar epithelium regeneration and enhance recovery from lung injury caused by bacterial pneumonia.